title: VEGF expression is augmented by hypoxia‑induced PGIS in human fibroblasts.
abstract: Prostacyclin synthase (PGIS or PTGIS) is an enzyme that catalyses the conversion of prostaglandin H2 (PGH2) to prostaglandin I2 (PGI2). PGI2 promotes cancer growth by activating peroxisome proliferator-activated receptor δ (PPARδ), and increases the expression levels of the pro-angiogenic factor vascular endothelial growth factor (VEGF). We found that the expression of the PGIS gene was enhanced in WI-38, TIG-3-20 and HEL human lung fibroblast cells and two cancer cell lines (NB-1 and G361) under hypoxic conditions. The main localization of PGIS changed from the cytoplasm to the nucleus by hypoxia in WI-38 cells. The induced PGIS had an enzymatic activity since the intracellular level of 6-keto-prostaglandin, a useful marker of PGI2 biosynthesis in vivo, was increased with the increasing levels of PGIS. Expression of VEGF was increased in parallel with PGIS induction under hypoxic conditions. PGIS knockdown resulted in the decreased expression of VEGF mRNA. Since VEGF is a known PPARδ target gene, we examined the effects of siRNAs targeting PPARδ on the expression of VEGF under hypoxic conditions. Knockdown of PPARδ suppressed the expression of VEGF under hypoxic conditions in WI-38 cells. These findings suggest that PGIS is induced by hypoxia and regulates the expression of VEGF in fibroblasts. Fibroblasts in the hypoxic area of tumors may have an important role in tumor growth and angiogenesis.
authors.affiliation: Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Jia
authors.initials: J
authors.lastname: Wang
authors.forename: Ryuji
authors.initials: R
authors.lastname: Ikeda
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Che
authors.forename: Akio
authors.initials: A
authors.lastname: Ooyama
authors.forename: Masatatsu
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Furukawa
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Hasui
authors.forename: Chun-Lei
authors.initials: CL
authors.lastname: Zheng
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tajitsu
authors.forename: Toshinori
authors.initials: T
authors.lastname: Oka
authors.forename: Sho
authors.initials: S
authors.lastname: Tabata
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Nishizawa
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Eizuru
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Akiyama
mesh_terms: D015687:Cell Hypoxia / Q000235:genetics*; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D011464:Epoprostenol / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis / Q000235:genetics*; D008168:Lung / Q000166:cytology / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics; D044262:Prostaglandin H2 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D047495:PPAR gamma; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D044262:Prostaglandin H2; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase